Skip to main content

Advertisement

SpringerLink
Log in

A genome scan for genes underlying adult body size differences between Central African hunter-gatherers and farmers

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

The evolutionary and biological bases of the Central African “pygmy” phenotype, a characteristic of rainforest hunter-gatherers defined by reduced body size compared with neighboring farmers, remain largely unknown. Here, we perform a joint investigation in Central African hunter-gatherers and farmers of adult standing height, sitting height, leg length, and body mass index (BMI), considering 358 hunter-gatherers and 169 farmers with genotypes for 153,798 SNPs. In addition to reduced standing heights, hunter-gatherers have shorter sitting heights and leg lengths and higher sitting/standing height ratios than farmers and lower BMI for males. Standing height, sitting height, and leg length are strongly correlated with inferred levels of farmer genetic ancestry, whereas BMI is only weakly correlated, perhaps reflecting greater contributions of non-genetic factors to body weight than to height. Single- and multi-marker association tests identify one region and eight genes associated with hunter-gatherer/farmer status, and 24 genes associated with the height-related traits. Many of these genes have putative functions consistent with roles in determining their associated traits and the pygmy phenotype, and they include three associated with standing height in non-Africans (PRKG1, DSCAM, MAGI2). We find evidence that European height-associated SNPs or variants in linkage disequilibrium with them contribute to standing- and sitting-height determination in Central Africans, but not to the differential status of hunter-gatherers and farmers. These findings provide new insights into the biological basis of the pygmy phenotype, and they highlight the potential of cross-population studies for exploring the genetic basis of phenotypes that vary naturally across populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Abubakari AR, Lauder W, Agyemang C, Jones M, Kirk A, Bhopal RS (2008) Prevalence and time trends in obesity among adult West African populations: a meta-analysis. Obes Rev 9:297–311

    Article  PubMed  CAS  Google Scholar 

  • Adams HH, Verlinden VJ, Callisaya ML, van Duijn CM, Hofman A, Thomson R, Uitterlinden AG, Vernooij MW, van der Geest JN, Srikanth V, Ikram MA (2016) Heritability and genome-wide association analyses of human gait suggest contribution of common variants. J Gerontol A Biol Sci Med Sci 71:740–746

    Article  PubMed  CAS  Google Scholar 

  • Aulchenko YS, Pullen J, Kloosterman WP, Yazdanpanah M, Hofman A, Vaessen N, Snijders PJ, Zubakov D, Mackay I, Olavesen M, Sidhu B, Smith VE, Carey A, Berezikov E, Uitterlinden AG, Plasterk RH, Oostra BA, van Duijn CM (2007) LPIN2 is associated with type 2 diabetes, glucose metabolism, and body composition. Diabetes 56:3020–3026

    Article  PubMed  CAS  Google Scholar 

  • Bahuchet S (1993a) L’invention des Pygmées. Cahiers d’Etudes africaines 33:153–181

    Article  Google Scholar 

  • Bahuchet S (1993b) La Rencontre des Agriculteurs. Les Pygmées parmi les Peuples d’Afrique Centrale, Paris

    Google Scholar 

  • Bahuchet S (2012) Changing language, remaining Pygmy. Hum Biol 84:11–43

    Article  PubMed  Google Scholar 

  • Bahuchet S, Guillaume H (1982) Aka-farmer relations in the Northwest Congo Basin. Cambridge University Press, Cambridge

    Google Scholar 

  • Bailey RC (1991) The comparative growth of Efe Pygmies and African farmers from birth to age 5 years. Ann Hum Biol 18:113–120

    Article  PubMed  CAS  Google Scholar 

  • Bailey RC, Head G, Tenike M, Owen B, Rechtman R, Zechenter E (1989) Hunting and gathering in tropical rainforest: is it possible? Am Anthropol 91:59–82

    Article  Google Scholar 

  • Balbas MD, Burgess MR, Murali R, Wongvipat J, Skaggs BJ, Mundel P, Weins A, Sawyers CL (2014) MAGI-2 scaffold protein is critical for kidney barrier function. Proc Natl Acad Sci USA 111:14876–14881

    Article  PubMed  CAS  Google Scholar 

  • Balding DJ, Nichols RA (1995) A method for quantifying differentiation between populations at multi-allelic loci and its implications for investigating identity and paternity. Genetica 96:3–12

    Article  PubMed  CAS  Google Scholar 

  • Bassett JH, Swinhoe R, Chassande O, Samarut J, Williams GR (2006) Thyroid hormone regulates heparan sulfate proteoglycan expression in the growth plate. Endocrinology 147:295–305

    Article  PubMed  CAS  Google Scholar 

  • Batini C, Lopes J, Behar DM, Calafell F, Jorde LB, van der Veen L, Quintana-Murci L, Spedini G, Destro-Bisol G, Comas D (2011) Insights into the demographic history of African Pygmies from complete mitochondrial genomes. Mol Biol Evol 28:1099–1110

    Article  PubMed  CAS  Google Scholar 

  • Becker NS, Verdu P, Froment A, Le Bomin S, Pagezy H, Bahuchet S, Heyer E (2011) Indirect evidence for the genetic determination of short stature in African Pygmies. Am J Phys Anthropol 145:390–401

    Article  PubMed  Google Scholar 

  • Becker NS, Verdu P, Georges M, Duquesnoy P, Froment A, Amselem S, Le Bouc Y, Heyer E (2013) The role of GHR and IGF1 genes in the genetic determination of African Pygmies’ short stature. Eur J Hum Genet 21:653–658

    Article  PubMed  CAS  Google Scholar 

  • Berndt SI, Gustafsson S, Magi R, Ganna A, Wheeler E, Feitosa MF, Justice AE, Monda KL, Croteau-Chonka DC, Day FR, Esko T, Fall T, Ferreira T, Gentilini D, Jackson AU, Luan J, Randall JC, Vedantam S, Willer CJ, Winkler TW et al (2013) Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nat Genet 45:501–512

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boehnke M, Cox NJ (1997) Accurate inference of relationships in sib-pair linkage studies. Am J Hum Genet 61:423–429

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bozzola M, Travaglino P, Marziliano N, Meazza C, Pagani S, Grasso M, Tauber M, Diegoli M, Pilotto A, Disabella E, Tarantino P, Brega A, Arbustini E (2009) The shortness of Pygmies is associated with severe under-expression of the growth hormone receptor. Mol Genet Metab 98:310–313

    Article  PubMed  CAS  Google Scholar 

  • Budarf ML, Konkle BA, Ludlow LB, Michaud D, Li M, Yamashiro DJ, McDonald-McGinn D, Zackai EH, Driscoll DA (1995) Identification of a patient with Bernard–Soulier syndrome and a deletion in the DiGeorge/velo-cardio-facial chromosomal region in 22q11.2. Hum Mol Genet 4:763–766

    Article  PubMed  CAS  Google Scholar 

  • Buschang PH, Malina RM, Little BB (1986) Linear growth of Zapotec schoolchildren: growth status and yearly velocity for leg length and sitting height. Ann Hum Biol 13:225–234

    Article  PubMed  CAS  Google Scholar 

  • Campos-Xavier AB, Martinet D, Bateman J, Belluoccio D, Rowley L, Tan TY, Baxova A, Gustavson KH, Borochowitz ZU, Innes AM, Unger S, Beckmann JS, Mittaz L, Ballhausen D, Superti-Furga A, Savarirayan R, Bonafe L (2009) Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair endochondral ossification and cause recessive omodysplasia. Am J Hum Genet 84:760–770

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carlson CS, Matise TC, North KE, Haiman CA, Fesinmeyer MD, Buyske S, Schumacher FR, Peters U, Franceschini N, Ritchie MD, Duggan DJ, Spencer KL, Dumitrescu L, Eaton CB, Thomas F, Young A, Carty C, Heiss G, Le Marchand L, Crawford DC et al (2013) Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. PLoS Biol 11:e1001661

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carty CL, Johnson NA, Hutter CM, Reiner AP, Peters U, Tang H, Kooperberg C (2012) Genome-wide association study of body height in African Americans: the Women’s Health Initiative SNP Health Association Resource (SHARe). Hum Mol Genet 21:711–720

    Article  PubMed  CAS  Google Scholar 

  • Cavalli-Sforza LL (1986) African Pygmies. Academic Press, Orlando

    Google Scholar 

  • Comuzzie AG, Cole SA, Laston SL, Voruganti VS, Haack K, Gibbs RA, Butte NF (2012) Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PLoS One 7:e51954

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Conrad DF, Jakobsson M, Coop G, Wen X, Wall JD, Rosenberg NA, Pritchard JK (2006) A worldwide survey of haplotype variation and linkage disequilibrium in the human genome. Nat Genet 38:1251–1260

    Article  PubMed  CAS  Google Scholar 

  • Darnell JE Jr (1997) STATs and gene regulation. Science 277:1630–1635

    Article  PubMed  CAS  Google Scholar 

  • de Garine I (1990) Adaptation biologique et bien-être psycho-culturel. Bulletins et Mémoires de la Société d 2:151–174

    Google Scholar 

  • de Filippo C, Bostoen K, Stoneking M, Pakendorf B (2012) Bringing together linguistic and genetic evidence to test the Bantu expansion. Proc Biol Sci 279:3256–3263

    Article  PubMed  PubMed Central  Google Scholar 

  • Destro-Bisol G, Donati F, Coia V, Boschi I, Verginelli F, Caglia A, Tofanelli S, Spedini G, Capelli C (2004) Variation of female and male lineages in sub-Saharan populations: the importance of sociocultural factors. Mol Biol Evol 21:1673–1682

    Article  PubMed  CAS  Google Scholar 

  • Devlin B, Roeder K (1999) Genomic control for association studies. Biometrics 55:997–1004

    Article  PubMed  CAS  Google Scholar 

  • Diamond JM (1991) Anthropology. Why are Pygmies small? Nature 354:111–112

    Article  PubMed  CAS  Google Scholar 

  • Dietz WH, Marino B, Peacock NR, Bailey RC (1989) Nutritional status of Efe pygmies and Lese horticulturists. Am J Phys Anthropol 78:509–518

    Article  PubMed  CAS  Google Scholar 

  • Epstein MP, Duren WL, Boehnke M (2000) Improved inference of relationship for pairs of individuals. Am J Hum Genet 67:1219–1231

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Falush D, Stephens M, Pritchard JK (2003) Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164:1567–1587

    PubMed  PubMed Central  CAS  Google Scholar 

  • Ferretti G, Atchou G, Grassi B, Marconi C, Cerretelli P (1993) Energetics of locomotion in African Pygmoids. Eur J Appl Physiol 62:7–10

    Article  Google Scholar 

  • Fezeu LK, Assah FK, Balkau B, Mbanya DS, Kengne AP, Awah PK, Mbanya JC (2008) Ten-year changes in central obesity and BMI in rural and urban Cameroon. Obesity (Silver Spring) 16:1144–1147

    Article  Google Scholar 

  • Fisher RA (1918) The correlation between relatives on the supposition of Mendelian inheritance. Trans R Soc Edinburgh 52:399–433

    Article  Google Scholar 

  • Froment A (1993) Adaptation biologique et variation dans l’espèce humaine: le cas des Pygmées d’Afrique. Bulletins et Mémoires de la Société d’Anthropologie de Paris 5:417–448

    Article  Google Scholar 

  • Froment A (2014) Human biology and health of African rainforest inhabitants. In: Hewlett BS (ed) Hunter-gatherers of the Congo Basin: cultures, histories, and biology of African Pygmies, 1st edn. Transaction Publishers, New Brunswick, pp 117–164

    Google Scholar 

  • Fürniss S, Bahuchet S (1995) Existe-t-il des instruments de musique pygmées ? In: Dehoux V, Fürniss S, Le Bomin S, Olivier E, Voisin F (eds) Ndroje balendro, musiques, terrains et disciplines (textes offerts à Simha Arom). Peters-Selaf, Paris, pp 87–109

    Google Scholar 

  • Geffner ME, Bersch N, Bailey RC, Golde DW (1995) Insulin-like growth factor I resistance in immortalized T cell lines from African Efe Pygmies. J Clin Endocrinol Metab 80:3732–3738

    Article  PubMed  CAS  Google Scholar 

  • Ghesquiere JL, Nkiama E (1993) Implications of small body size to strength and endurance of Pygmy and village children in the Ituri Forest. In: 4th World conference on human ecology, Merida, Mexico

  • Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, Sulem P, Thorlacius S, Gylfason A, Steinberg S, Helgadottir A, Ingason A, Steinthorsdottir V, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T et al (2008) Many sequence variants affecting diversity of adult human height. Nat Genet 40:609–615

    Article  PubMed  CAS  Google Scholar 

  • Hagino I, Hayashi K, Kawamura K, Sato H, Yamauchi T (2013) Adolescent growth spurt and growth pattern factors related to the short stature of Pygmy hunter-gatherers of Southeast Cameroon. Ann Hum Biol 40:9–14

    Article  PubMed  Google Scholar 

  • Hattori Y, Vera JC, Rivas CI, Bersch N, Bailey RC, Geffner ME, Golde DW (1996) Decreased insulin-like growth factor I receptor expression and function in immortalized African Pygmy T cells. J Clin Endocrinol Metab 81:2257–2263

    PubMed  CAS  Google Scholar 

  • Hattori D, Demir E, Kim HW, Viragh E, Zipursky SL, Dickson BJ (2007) Dscam diversity is essential for neuronal wiring and self-recognition. Nature 449:223–227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hauspie RC, Pagezy H (1989) Longitudinal study of growth of African babies: an analysis of seasonal variations in the average growth rate and the effects of infectious diseases on individual and average growth patterns. Acta Paediatr Scand Suppl 350:37–43

    Article  PubMed  CAS  Google Scholar 

  • Hemani G, Yang J, Vinkhuyzen A, Powell JE, Willemsen G, Hottenga JJ, Abdellaoui A, Mangino M, Valdes AM, Medland SE, Madden PA, Heath AC, Henders AK, Nyholt DR, de Geus EJ, Magnusson PK, Ingelsson E, Montgomery GW, Spector TD, Boomsma DI et al (2013) Inference of the genetic architecture underlying BMI and height with the use of 20,240 sibling pairs. Am J Hum Genet 93:865–875

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hewlett BS (1996) Cultural diversity among African Pygmies. In: Kent S (ed) Cultural diversity among twentieth-century foragers: An African perspective, vol 1. Cambridge University Press, Cambridge, pp 215–244

    Google Scholar 

  • Hewlett BS (2014) Introduction. Hunter-gatherers of the Congo Basin: cultures, histrories, and biology of African Pygmies. Transaction Publishers, New Brunswick, pp vxii–xxix

    Google Scholar 

  • Hiernaux J (1974) The people of Africa. Weidenfeld and Nicolson, London

    Google Scholar 

  • Hiernaux J (1977) Long-term biological effects of human migrations from the African savanna to the equitorial forest: a case study of human adaption to a hot and wet climate. In: Harrison GA (ed) Population structure and human variation. Cambridge University Press, London, pp 187–217

    Google Scholar 

  • Hintze JL, Nelson RD (1998) Violin plots: a box plot-density trace synergism. Am Stat 52:181–184

    Google Scholar 

  • Hsieh P, Veeramah KR, Lachance J, Tishkoff SA, Wall JD, Hammer MF, Gutenkunst RN (2016) Whole-genome sequence analyses of Western Central African Pygmy hunter-gatherers reveal a complex demographic history and identify candidate genes under positive natural selection. Genome Res 26:279–290

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Huang L, Jakobsson M, Pemberton TJ, Ibrahim M, Nyambo T, Omar S, Pritchard JK, Tishkoff SA, Rosenberg NA (2011) Haplotype variation and genotype imputation in African populations. Genet Epidemiol 35:766–780

    Article  PubMed  PubMed Central  Google Scholar 

  • Huxley JS (1932) Problems of relative growth. Methuen and Company Ltd, London

    Google Scholar 

  • Jakobsson M, Rosenberg NA (2007) CLUMPP: a cluster matching and permutation program for dealing with label switching and multimodality in analysis of population structure. Bioinformatics 23:1801–1806

    Article  PubMed  CAS  Google Scholar 

  • Jarvis JP, Scheinfeldt LB, Soi S, Lambert C, Omberg L, Ferwerda B, Froment A, Bodo JM, Beggs W, Hoffman G, Mezey J, Tishkoff SA (2012) Patterns of ancestry, signatures of natural selection, and genetic association with stature in Western African Pygmies. PLoS Genet 8:e1002641

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Joiris D (2003) The framework of Central African hunter-gatherers and neighbouring societies. Afr Stud Monogr 28:57–79

    Google Scholar 

  • Kang HM, Sul JH, Service SK, Zaitlen NA, Kong SY, Freimer NB, Sabatti C, Eskin E (2010) Variance component model to account for sample structure in genome-wide association studies. Nat Genet 42:348–354

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Katzmarzyk PT, Leonard WR (1998) Climatic influences on human body size and proportions: ecological adaptations and secular trends. Am J Phys Anthropol 106:483–503

    Article  PubMed  CAS  Google Scholar 

  • Kim HN, Lee EJ, Jung SC, Lee JY, Chung HW, Kim HL (2010) Genetic variants that affect length/height in infancy/early childhood in Vietnamese-Korean families. J Hum Genet 55:681–690

    Article  PubMed  Google Scholar 

  • Ko J, Na M, Kim S, Lee JR, Kim E (2003) Interaction of the ERC family of RIM-binding proteins with the liprin-alpha family of multidomain proteins. J Biol Chem 278:42377–42385

    Article  PubMed  CAS  Google Scholar 

  • Lachance J, Vernot B, Elbers CC, Ferwerda B, Froment A, Bodo JM, Lema G, Fu W, Nyambo TB, Rebbeck TR, Zhang K, Akey JM, Tishkoff SA (2012) Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse african hunter-gatherers. Cell 150:457–469

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, Ferreira T, Wood AR, Weyant RJ, Segre AV, Speliotes EK, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D et al (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467:832–838

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Le Bomin S, Mbot J (2012) The musical heritage of the Gabon Bongo. Before Farming 2012/1 article 3:1–19

    Article  Google Scholar 

  • Lemogoum D, Ngatchou W, Janssen C, Leeman M, Van Bortel L, Boutouyrie P, Degaute JP, Van de Borne P (2012) Effects of hunter-gatherer subsistence mode on arterial distensibility in Cameroonian pygmies. Hypertension 60:123–128

    Article  PubMed  CAS  Google Scholar 

  • Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, Eyheramendy S, Voight BF, Butler JL, Guiducci C, Illig T, Hackett R, Heid IM, Jacobs KB, Lyssenko V, Uda M, Boehnke M, Chanock SJ, Groop LC, Hu FB et al (2008) Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 40:584–591

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li Z, Xi X, Gu M, Feil R, Ye RD, Eigenthaler M, Hofmann F, Du X (2003) A stimulatory role for cGMP-dependent protein kinase in platelet activation. Cell 112:77–86

    Article  PubMed  CAS  Google Scholar 

  • Li MJ, Wang LY, Xia Z, Sham PC, Wang J (2013) GWAS3D: detecting human regulatory variants by integrative analysis of genome-wide associations, chromosome interactions and histone modifications. Nucleic Acids Res 41:W150–W158

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu JZ, McRae AF, Nyholt DR, Medland SE, Wray NR, Brown KM, Investigators A, Hayward NK, Montgomery GW, Visscher PM, Martin NG, Macgregor S (2010) A versatile gene-based test for genome-wide association studies. Am J Hum Genet 87:139–145

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lopez M, Tena-Sempere M (2016) Estradiol and brown fat. Best Pract Res Clin Endocrinol Metab 30:527–536

    Article  PubMed  CAS  Google Scholar 

  • Lopez M, Kousathanas A, Quach H, Harmant C, Mouguiama-Daouda P, Hombert JM, Froment A, Perry GH, Barreiro LB, Verdu P, Patin E, Quintana-Murci L (2018) The demographic history and mutational load of African hunter-gatherers and farmers. Nat Ecol Evol 2:721–730

    Article  PubMed  Google Scholar 

  • Maas NM, Van de Putte T, Melotte C, Francis A, Schrander-Stumpel CT, Sanlaville D, Genevieve D, Lyonnet S, Dimitrov B, Devriendt K, Fryns JP, Vermeesch JR (2007) The C20orf133 gene is disrupted in a patient with Kabuki syndrome. J Med Genet 44:562–569

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Marchini J, Cardon LR, Phillips MS, Donnelly P (2004) The effects of human population structure on large genetic association studies. Nat Genet 36:512–517

    Article  PubMed  CAS  Google Scholar 

  • Martin AR, Gignoux CR, Walters RK, Wojcik GL, Neale BM, Gravel S, Daly MJ, Bustamante CD, Kenny EE (2017) Human demographic history impacts genetic risk prediction across diverse populations. Am J Hum Genet 100:635–649

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Merimee TJ, Rimoin DL, Cavalli-Sforza LL (1972) Metabolic studies in the African Pygmy. J Clin Investig 51:395–401

    Article  PubMed  CAS  Google Scholar 

  • Merimee TJ, Zapf J, Hewlett B, Cavalli-Sforza LL (1987) Insulin-like growth factors in Pygmies. The role of puberty in determining final stature. N Engl J Med 316:906–911

    Article  PubMed  CAS  Google Scholar 

  • Meyer LR, Zweig AS, Hinrichs AS, Karolchik D, Kuhn RM, Wong M, Sloan CA, Rosenbloom KR, Roe G, Rhead B, Raney BJ, Pohl A, Malladi VS, Li CH, Lee BT, Learned K, Kirkup V, Hsu F, Heitner S, Harte RA et al (2013) The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res 41:D64–D69

    Article  PubMed  CAS  Google Scholar 

  • Migliano AB, Vinicius L, Lahr MM (2007) Life history trade-offs explain the evolution of human Pygmies. Proc Natl Acad Sci USA 104:20216–20219

    Article  PubMed  Google Scholar 

  • Montano V, Ferri G, Marcari V, Batini C, Anyaele O, Destro-Bisol G, Comas D (2011) The Bantu expansion revisited: a new analysis of Y chromosome variation in Central Western Africa. Mol Ecol 20:2693–2708

    Article  PubMed  Google Scholar 

  • N’Diaye A, Chen GK, Palmer CD, Ge B, Tayo B, Mathias RA, Ding J, Nalls MA, Adeyemo A, Adoue V, Ambrosone CB, Atwood L, Bandera EV, Becker LC, Berndt SI, Bernstein L, Blot WJ, Boerwinkle E, Britton A, Casey G et al (2011) Identification, replication, and fine-mapping of loci associated with adult height in individuals of African ancestry. PLoS Genet 7:e1002298

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ober C, Abney M, McPeek MS (2001) The genetic dissection of complex traits in a founder population. Am J Hum Genet 69:1068–1079

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ohenjo N, Willis R, Jackson D, Nettleton C, Good K, Mugarura B (2006) Health of Indigenous people in Africa. Lancet 367:1937–1946

    Article  PubMed  Google Scholar 

  • Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC, Mundlos S, Shibuya H, Takada S, Minami Y (2003) The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8:645–654

    Article  PubMed  CAS  Google Scholar 

  • Patin E, Laval G, Barreiro LB, Salas A, Semino O, Santachiara-Benerecetti S, Kidd KK, Kidd JR, Van der Veen L, Hombert JM, Gessain A, Froment A, Bahuchet S, Heyer E, Quintana-Murci L (2009) Inferring the demographic history of African farmers and Pygmy hunter-gatherers using a multilocus resequencing data set. PLoS Genet 5:e1000448

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Patin E, Siddle KJ, Laval G, Quach H, Harmant C, Becker N, Froment A, Regnault B, Lemee L, Gravel S, Hombert JM, Van der Veen L, Dominy NJ, Perry GH, Barreiro LB, Verdu P, Heyer E, Quintana-Murci L (2014) The impact of agricultural emergence on the genetic history of African rainforest hunter-gatherers and agriculturalists. Nat Commun 5:3163

    Article  PubMed  CAS  Google Scholar 

  • Patin E, Lopez M, Grollemund R, Verdu P, Harmant C, Quach H, Laval G, Perry GH, Barreiro LB, Froment A, Heyer E, Massougbodji A, Fortes-Lima C, Migot-Nabias F, Bellis G, Dugoujon JM, Pereira JB, Fernandes V, Pereira L, Van der Veen L et al (2017) Dispersals and genetic adaptation of Bantu-speaking populations in Africa and North America. Science 356:543–546

    Article  PubMed  CAS  Google Scholar 

  • Pemberton TJ, Wang C, Li JZ, Rosenberg NA (2010) Inference of unexpected genetic relatedness among individuals in HapMap Phase III. Am J Hum Genet 87:457–464

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Perola M, Sammalisto S, Hiekkalinna T, Martin NG, Visscher PM, Montgomery GW, Benyamin B, Harris JR, Boomsma D, Willemsen G, Hottenga JJ, Christensen K, Kyvik KO, Sorensen TI, Pedersen NL, Magnusson PK, Spector TD, Widen E, Silventoinen K, Kaprio J et al (2007) Combined genome scans for body stature in 6,602 European twins: evidence for common Caucasian loci. PLoS Genet 3:e97

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Perry GH, Dominy NJ (2009) Evolution of the human pygmy phenotype. Trends Ecol Evol 24:218–225

    Article  PubMed  Google Scholar 

  • Perry GH, Foll M, Grenier JC, Patin E, Nedelec Y, Pacis A, Barakatt M, Gravel S, Zhou X, Nsobya SL, Excoffier L, Quintana-Murci L, Dominy NJ, Barreiro LB (2014a) Adaptive, convergent origins of the pygmy phenotype in African rainforest hunter-gatherers. Proc Natl Acad Sci USA 111:E3596–E3603

    Article  PubMed  CAS  Google Scholar 

  • Perry JR, Day F, Elks CE, Sulem P, Thompson DJ, Ferreira T, He C, Chasman DI, Esko T, Thorleifsson G, Albrecht E, Ang WQ, Corre T, Cousminer DL, Feenstra B, Franceschini N, Ganna A, Johnson AD, Kjellqvist S, Lunetta KL et al (2014b) Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 514:92–97

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pfeifer A, Klatt P, Massberg S, Ny L, Sausbier M, Hirneiss C, Wang GX, Korth M, Aszodi A, Andersson KE, Krombach F, Mayerhofer A, Ruth P, Fassler R, Hofmann F (1998) Defective smooth muscle regulation in cGMP kinase I-deficient mice. EMBO J 17:3045–3051

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959

    PubMed  PubMed Central  CAS  Google Scholar 

  • Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abecasis GR, Willer CJ (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26:2336–2337

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Quintana-Murci L, Quach H, Harmant C, Luca F, Massonnet B, Patin E, Sica L, Mouguiama-Daouda P, Comas D, Tzur S, Balanovsky O, Kidd KK, Kidd JR, van der Veen L, Hombert JM, Gessain A, Verdu P, Froment A, Bahuchet S, Heyer E et al (2008) Maternal traces of deep common ancestry and asymmetric gene flow between Pygmy hunter-gatherers and Bantu-speaking farmers. Proc Natl Acad Sci USA 105:1596–1601

    Article  PubMed  Google Scholar 

  • R Development Core Team (2014) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna

    Google Scholar 

  • Ramirez Rozzi FV, Sardi ML (2010) Diversity among African pygmies. PLoS One 5:e13620

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rimoin DL, Merimee TJ, Rabinowitz D, Cavalli-Sforza LL, McKusick VA (1969) Peripheral subresponsiveness to human growth hormone in the African Pygmies. N Engl J Med 281:1383–1388

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg NA (2004) distruct: a program for the graphical display of population structure. Mol Ecol Notes 4:137–138

    Article  Google Scholar 

  • Rozzi FV, Koudou Y, Froment A, Le Bouc Y, Botton J (2015) Growth pattern from birth to adulthood in African pygmies of known age. Nat Commun 6:7672

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Samaan G, Yugo D, Rajagopalan S, Wall J, Donnell R, Goldowitz D, Gopalakrishnan R, Venkatachalam S (2010) Foxn3 is essential for craniofacial development in mice and a putative candidate involved in human congenital craniofacial defects. Biochem Biophys Res Commun 400:60–65

    Article  PubMed  CAS  Google Scholar 

  • Schmeisser MJ, Ey E, Wegener S, Bockmann J, Stempel AV, Kuebler A, Janssen AL, Udvardi PT, Shiban E, Spilker C, Balschun D, Skryabin BV, Dieck S, Smalla KH, Montag D, Leblond CS, Faure P, Torquet N, Le Sourd AM, Toro R et al (2012) Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486:256–260

    Article  PubMed  CAS  Google Scholar 

  • Seeman E (1998) Growth in bone mass and size—are racial and gender differences in bone mineral density more apparent than real? J Clin Endocrinol Metab 83:1414–1419

    PubMed  CAS  Google Scholar 

  • Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J (2003) Triggering the interferon antiviral response through an IKK-related pathway. Science 300:1148–1151

    Article  PubMed  CAS  Google Scholar 

  • Shea BT, Bailey RC (1996) Allometry and adaptation of body proportions and stature in African pygmies. Am J Phys Anthropol 100:311–340

    Article  PubMed  CAS  Google Scholar 

  • Shriner D, Adeyemo A, Gerry NP, Herbert A, Chen G, Doumatey A, Huang H, Zhou J, Christman MF, Rotimi CN (2009) Transferability and fine-mapping of genome-wide associated loci for adult height across human populations. PLoS One 4:e8398

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Silventoinen K, Kaprio J, Lahelma E, Koskenvuo M (2000) Relative effect of genetic and environmental factors on body height: differences across birth cohorts among Finnish men and women. Am J Public Health 90:627–630

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Soranzo N, Rivadeneira F, Chinappen-Horsley U, Malkina I, Richards JB, Hammond N, Stolk L, Nica A, Inouye M, Hofman A, Stephens J, Wheeler E, Arp P, Gwilliam R, Jhamai PM, Potter S, Chaney A, Ghori MJ, Ravindrarajah R, Ermakov S et al (2009) Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size. PLoS Genet 5:e1000445

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT (2005) Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci USA 102:8089–8096

    Article  PubMed  CAS  Google Scholar 

  • The International HapMap Consortium (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861

    Article  PubMed Central  CAS  Google Scholar 

  • Tupman GS (1962) A study of bone growth in normal children and its relationship to skeletal maturation. J Bone Jt Surg Br 44-B:42–67

    Article  CAS  Google Scholar 

  • Turnbull C (1965) Wayward servants, the two worlds of the African Pygmies. The Natural History Press, New York

    Google Scholar 

  • Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW (1997) Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci USA 94:7239–7244

    Article  PubMed  CAS  Google Scholar 

  • van Kuilenburg AB, Meijer J, Mul AN, Hennekam RC, Hoovers JM, de Die-Smulders CE, Weber P, Mori AC, Bierau J, Fowler B, Macke K, Sass JO, Meinsma R, Hennermann JB, Miny P, Zoetekouw L, Vijzelaar R, Nicolai J, Ylstra B, Rubio-Gozalbo ME (2009) Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3). Hum Genet 125:581–590

    Article  PubMed  CAS  Google Scholar 

  • Verdu P (2009) Anthropologie génétique des populations humaines d’Afrique Centrale: histoire du peuplement Pygmée. Ph.D. thesis, Université Pierre-et-Marie-Curie, Paris, France

  • Verdu P, Austerlitz F, Estoup A, Vitalis R, Georges M, Thery S, Froment A, Le Bomin S, Gessain A, Hombert JM, Van der Veen L, Quintana-Murci L, Bahuchet S, Heyer E (2009) Origins and genetic diversity of Pygmy hunter-gatherers from Western Central Africa. Curr Biol 19:312–318

    Article  PubMed  CAS  Google Scholar 

  • Verdu P, Becker NS, Froment A, Georges M, Grugni V, Quintana-Murci L, Hombert JM, Van der Veen L, Le Bomin S, Bahuchet S, Heyer E, Austerlitz F (2013) Sociocultural behavior, sex-biased admixture, and effective population sizes in Central African Pygmies and non-Pygmies. Mol Biol Evol 30:918–937

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Voight BF, Kang HM, Ding J, Palmer CD, Sidore C, Chines PS, Burtt NP, Fuchsberger C, Li Y, Erdmann J, Frayling TM, Heid IM, Jackson AU, Johnson T, Kilpelainen TO, Lindgren CM, Morris AP, Prokopenko I, Randall JC, Saxena R et al (2012) The Metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet 8:e1002793

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wadsworth ME, Hardy RJ, Paul AA, Marshall SF, Cole TJ (2002) Leg and trunk length at 43 years in relation to childhood health, diet and family circumstances; evidence from the 1946 national birth cohort. Int J Epidemiol 31:383–390

    Article  PubMed  CAS  Google Scholar 

  • Waldman LA, Chia DJ (2013) Towards identification of molecular mechanisms of short stature. Int J Pediatr Endocrinol 2013:19

    Article  PubMed  PubMed Central  Google Scholar 

  • Weedon MN, Lango H, Lindgren CM, Wallace C, Evans DM, Mangino M, Freathy RM, Perry JR, Stevens S, Hall AS, Samani NJ, Shields B, Prokopenko I, Farrall M, Dominiczak A, Johnson T, Bergmann S, Beckmann JS, Vollenweider P, Waterworth DM et al (2008) Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 40:575–583

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weiner JS, Lourie JA (1981) Practical human biology. Academic Press, London

    Google Scholar 

  • Weir BS (1996) Genetic data analysis II. Sinauer, Sunderland

    Google Scholar 

  • Wolf SF, Sieburth D, Sypek J (1994) Interleukin 12: a key modulator of immune function. Stem Cells 12:154–168

    Article  PubMed  CAS  Google Scholar 

  • Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, Chu AY, Estrada K, Luan J, Kutalik Z, Amin N, Buchkovich ML, Croteau-Chonka DC, Day FR, Duan Y, Fall T, Fehrmann R, Ferreira T, Jackson AU, Karjalainen J et al (2014) Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet 46:1173–1186

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yiu GK, Kaunisto A, Chin YR, Toker A (2011) NFAT promotes carcinoma invasive migration through glypican-6. Biochem J 440:157–166

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yu J, Pressoir G, Briggs WH, Vroh Bi I, Yamasaki M, Doebley JF, McMullen MD, Gaut BS, Nielsen DM, Holland JB, Kresovich S, Buckler ES (2006) A unified mixed-model method for association mapping that accounts for multiple levels of relatedness. Nat Genet 38:203–208

    Article  PubMed  CAS  Google Scholar 

  • Zaitlen N, Kraft P, Patterson N, Pasaniuc B, Bhatia G, Pollack S, Price AL (2013) Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits. PLoS Genet 9:e1003520

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the volunteers from Cameroon, Central African Republic, Gabon, and Uganda who participated in this study. They thank Peter Chines for providing independently verified Cardio-MetaboChip SNP positions, Sen Li for providing ancestral and derived allelic states for the MetaboChip SNPs, Hyun Min Kang for EMMAX assistance, and Frédéric Austerlitz, Erkan Buzbas, Zachary Szpiech, and Lawrence Uricchio for useful comments and discussions. This investigation was supported by the France-Stanford Center for Interdisciplinary Studies (N. A. R.); the French Assistance Publique Hôpitaux de Paris, ATM-MNHN ‘Les relations Sociétés-Natures dans le long terme’ 2009–2012 and the Fondation pour la Recherche Médicale and the ANR-Blanc program ‘GrowingAP’ (E. H.); a University of Michigan Center for Genetics in Health and Medicine postdoctoral fellowship (T. J. P.); and a Natural Sciences and Engineering Research Council of Canada Discovery Grant (RGPIN-2015-04739; T. J. P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. Trevor J. Pemberton and Paul Verdu contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada

    Trevor J. Pemberton

  2. CNRS-MNHN-Université Paris Diderot, UMR 7206 Eco-Anthropologie et Ethnobiologie, Paris, France

    Paul Verdu, Sylvie Le Bomin & Evelyne Heyer

  3. Division of Evolutionary Biology, Faculty of Biology, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany

    Noémie S. Becker

  4. Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA

    Cristen J. Willer

  5. Department of Anthropology, Washington State University, Vancouver, WA, USA

    Barry S. Hewlett

  6. IRD–MNHN, UMR 208 Patrimoines locaux, Paris, France

    Alain Froment

  7. Department of Biology, Stanford University, Stanford, CA, USA

    Noah A. Rosenberg

Authors
  1. Trevor J. Pemberton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul Verdu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noémie S. Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cristen J. Willer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barry S. Hewlett
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sylvie Le Bomin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alain Froment
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Noah A. Rosenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Evelyne Heyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Trevor J. Pemberton, Paul Verdu, Noah A. Rosenberg or Evelyne Heyer.

Ethics declarations

Ethics approval and consent to participate

The study was conducted according to ethical principles of the Declaration of Helsinki. IRB approvals were obtained from the French Ministry of Higher Education and Research (2005, renewed in 2010 and 2016), Stanford (2012) and Washington State Universities (2007), and the Universities of Manitoba (2013) and Michigan (2010). Prior to sample collection, research authorizations were obtained from the Ministry of Public Health in Cameroon (2005; renewed 2010), the Ministry of Higher Education and Research in Gabon (2006 and 2007), the National Council for Science and Technology in Uganda (2007), and the Ministry of Scientific Research in the Central African Republic (2007). Informed consent was obtained from all participants.

Conflict of interest

The authors declare that they have no conflicts of interest.

Availability of data and material

The Illumina Cardio-MetaboChip SNP genotype datasets for the 406 unrelated individuals analyzed are available in the European Genome-Phenome archive (EGAS00001002975) and will be accessible for population-genetic studies of demography and natural selection as well as for anthropological-genetic studies of the genetic determination of anthropometrical phenotypic features in accordance with the informed consent documents used in the recruitment of individuals who participated in this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 3810 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pemberton, T.J., Verdu, P., Becker, N.S. et al. A genome scan for genes underlying adult body size differences between Central African hunter-gatherers and farmers. Hum Genet 137, 487–509 (2018). https://doi.org/10.1007/s00439-018-1902-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-018-1902-3

Search

Navigation